Fluocinolone Implants to Protect Against Undesirable Bone and Cartilage Destruction

ABSTRACT

Effective treatments for protecting against undesirable macrophage activity are provided. Through the administration of an effective amount of fluocinolone at or near a target site, one can reduce or prevent macrophage activity. In various embodiments, fluocinolone formulations may be provided within biodegradable polymers to prevent transplant rejection for at least thirty days. In some embodiments, the relief can be for at least sixty days, or up to ninety days.

This application claims the benefit of the filing date of U.S.Provisional Patent Application No. 61/046,218 filed Apr. 18, 2008 andentitled “Fluocinolone Formulations In A Biodegradable Polymer Carrier.”U.S. Provisional Patent Application No. 61/046,218 is herebyincorporated by reference into the present disclosure.

BACKGROUND

Macrophage cells provide the human body with the ability to clear out orto remove dead or decaying cells. Their primary mechanism foraccomplishing this task is to engulf and then to digest cellular debrisand pathogens, and they can act as either stationary or mobile cells,and stimulate lymphocytes and other immune cells to respond topathogens. In many circumstances this is a highly desirable action.

However, macrophages can also target materials in the body that the hostorganism would prefer were left in place. For example, macrophage cellshave been indicated as the major mechanism through which inflammatorycytokines are produced in rheumatic arthritis and in turn can lead tothe deleterious removal of cartilage. Macrophages have also beenimplicated in the immunologically distinct condition of osteoarthritis.

To date interventions for conditions such as rheumatoid arthritis andosteoarthritis have focused on treating the resulting inflammation andpain but not the upstream causes of these symptoms. Thus, although thismay provide some relief from the symptoms of inflammation and pain;however, the underlying condition remains a problem. Accordingly, thereis a need to provide effective treatments to prevent undesirablemacrophage recruitment, which in turn may prevent the production ofsubstances that cause the problems such as the inflammatory cytokines.

SUMMARY

Fluocinolone is a corticosteroid that in known to have anti-inflammatoryproperties. However, the present inventors have appreciated that it mayalso be used to reduce or to prevent undesirable macrophage activityupstream of the inflammatory response by minimizing macrophagerecruitment in the first place, which is implicated in diseases such asarthritis. Accordingly, the present application provides compositionscomprising fluocinolone or its pharmaceutically acceptable salts thatare administered in order to reduce or to prevent destruction of boneand/or cartilage and thus has an osteoprotective effect or protects thecartilage as it reduces undesirable macrophage present and subsequentactivity. The present application also provides methods of treatmentthat use these materials. In various embodiments, the fluocinolone orits pharmaceutically acceptable salt may be administered to reduce or toprevent arthritic conditions. In some embodiments, these compositionsand methods may be designed for long duration release of fluocinolonethat has been internally placed.

According to one embodiment, there is a pharmaceutical formulationcomprising: fluocinolone, wherein the fluocinolone or a pharmaceuticallyacceptable salt thereof comprises from about 300 micrograms to about 350micrograms of the formulation, and at least one biodegradable polymer.The pharmaceutical composition may for example, be part of a drug depot.The drug depot may: (i) consist of only the fluocinolone (or one or moreof its pharmaceutically acceptable salts) and the biodegradablepolymer(s); or (ii) consist essentially of the fluocinolone (or one ormore of its pharmaceutically acceptable salts) and the biodegradablepolymer(s); or (iii) comprise the fluocinolone (or one or more of itspharmaceutically acceptable salts), the biodegradable polymer(s) and oneor more other active ingredients, surfactants, excipients or otheringredients or combinations thereof. When there are other activeingredients, surfactants, excipients or other ingredients orcombinations thereof in the formulation, in some embodiments these othercompounds or combinations thereof comprise less than 20 wt. %, less than19 wt. %, less than 18 wt. %, less than 17 wt. %, less than 16 wt. %,less than 15 wt. %, less than 14 wt. %, less than 13 wt. %, less than 12wt. %, less than 11 wt. %, less than 10 wt. %, less than 9 wt. %, lessthan 8 wt. %, less than 7 wt. %, less than 6 wt. %, less than 5 wt. %,less than 4 wt. %, less than 3 wt. %, less than 2 wt. %, less than 1 wt.% or less than 0.5 wt. % of the formulation.

According to another embodiment, there is a pharmaceutical formulationcomprising fluocinolone or a pharmaceutically acceptable salt thereof,wherein the fluocinolone or a pharmaceutically acceptable salt thereofcomprises from about 0.5 wt. % to about 20 wt. % of the formulation, andat least one biodegradable polymer, wherein the at least onebiodegradable polymer comprises poly(lactic-co-glycolic acid) orpoly(orthoester) or a combination thereof, and the at least onebiodegradable polymer comprises at least 80 wt. % of the formulation.

According to another embodiment, there is an implantable drug depot forreducing or preventing bone and/or cartilage destruction in a patient inneed of such treatment, the implantable drug depot comprisingfluocinolone or a pharmaceutically acceptable salt thereof in an amountfrom about 0.05 wt. % to about 25 wt. % of the formulation, and at leastone biodegradable polymer.

According to another embodiment, there is an implantable drug depot forreducing or preventing bone and/or cartilage destruction in a patient inneed of such treatment, the implantable drug depot comprisingfluocinolone or a pharmaceutically acceptable salt thereof in an amountof from about 0.5 wt. % to about 20 wt. % of the drug depot, and atleast one biodegradable polymer, wherein the at least one biodegradablepolymer comprises poly(lactic-co-glycolic acid) or poly(orthoester) or acombination thereof, and said at least one biodegradable polymercomprises at least 80 wt. % of said formulation.

According to another embodiment, there is an implantable drug depot forreducing or preventing bone and/or cartilage destruction in a patient inneed of such treatment, the implantable drug depot comprisingfluocinolone or a pharmaceutically acceptable salt thereof in an amountof from about 0.5 wt. % to about 25 wt. % of the drug depot, and atleast one polymer, wherein the at least one polymer comprises one ormore of poly(lactide-co-glycolide), D-lactide, D,L-lactide, L-lactide,D,L-lactide-caprolactone, and D,L-lactide-glycolide-caprolactone.

According to another embodiment, there is a method of making animplantable drug depot, the method comprising combining a biocompatiblepolymer and a therapeutically effective amount of the fluocinolone or apharmaceutically acceptable salt thereof and forming the implantabledrug depot from the combination.

Additional features and advantages of various embodiments will be setforth in part in the description that follows, and in part will beapparent from the description, or may be learned by practice of variousembodiments. The objectives and other advantages of various embodimentswill be realized and attained by means of the elements and combinationsparticularly pointed out in the description and appended claims.

BRIEF DESCRIPTION OF THE DRAWINGS

In part, other aspects, features, benefits and advantages of theembodiments will be apparent with regard to the following description,appended claims.

FIG. 1 is representation of the NP (nucleus pulposus taken from theinter-vertebral disc from the spinal cord) of the layout of the slidesthat appear in FIGS. 2-12.

FIG. 2 is a representation of a slide taken from Animal 267 at 4×objective.

FIG. 3 is a representation of a slide taken from Animal 267 at 10×objective.

FIG. 4 is a representation of a slide taken from Animal 267 at 20×objective.

FIG. 5 is a representation of a slide taken from Animal 266 at 4×objective.

FIG. 6 is a representation of a slide taken from Animal 266 at 10×objective.

FIG. 7 is a representation of a slide taken from Animal 266 at 20×objective.

FIG. 8 is a representation of a slide taken from Animal 265 at 4×objective.

FIG. 9 is a representation of a slide taken from Animal 265 at 10×objective.

FIG. 10 is a representation of a slide taken from Animal 265 at 20×objective.

FIG. 11 is a representation of a slide taken from Animal 267D at 4×objective.

FIG. 12 is a representation of a slide taken from Animal 267D at 10× andat 20× objective.

DETAILED DESCRIPTION

For the purposes of this specification and appended claims, unlessotherwise indicated, all numbers expressing quantities of ingredients,percentages or proportions of materials, reaction conditions, and othernumerical values used in the specification and claims, are to beunderstood as being modified in all instances by the term “about.”Accordingly, unless indicated to the contrary, the numerical parametersset forth in the following specification and attached claims areapproximations that may vary depending upon the desired propertiessought to be obtained by the present invention. At the very least, andnot as an attempt to limit the application of the doctrine ofequivalents to the scope of the claims, each numerical parameter shouldat least be construed in light of the number of reported significantdigits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forththe broad scope of the invention are approximations, the numericalvalues set forth in the specific examples are reported as precisely aspossible. Any numerical value, however, inherently contains certainerrors necessarily resulting from the standard deviation found in theirrespective testing measurements. Moreover, all ranges disclosed hereinare to be understood to encompass any and all subranges subsumedtherein. For example, a range of “1 to 10” includes any and allsubranges between (and including) the minimum value of 1 and the maximumvalue of 10, that is, any and all subranges having a minimum value ofequal to or greater than 1 and a maximum value of equal to or less than10, e.g., 5.5 to 10.

Definitions

It is noted that, as used in this specification and the appended claims,the singular forms “a,” “an,” and “the,” include plural referents unlessexpressly and unequivocally limited to one referent. Thus, for example,reference to “a drug depot” includes one, two, three or more drugdepots.

A “drug depot” is the composition in which the fluocinolone isadministered to the body. Thus, a drug depot may comprise a physicalstructure to facilitate implantation and retention in a desired site.The drug depot also comprises the drug itself. The term “drug” as usedherein is generally meant to refer to any substance that alters thephysiology of a patient. The term “drug” may be used interchangeablyherein with the terms “therapeutic agent,” “therapeutically effectiveamount,” and “active pharmaceutical ingredient” or “API.” It will beunderstood that unless otherwise specified a “drug” formulation mayinclude more than one therapeutic agent, wherein exemplary combinationsof therapeutic agents include a combination of two or more drugs. Thedrug provides a concentration gradient of the therapeutic agent fordelivery to the site. In various embodiments, the drug depot provides anoptimal drug concentration gradient of the therapeutic agent at adistance of up to about 0.01 cm to about 10 cm from the administrationsite and comprises fluocinolone. A drug depot may also include a pump orpellet. In some embodiments, the drug depot has pores that allow releaseof the drug from the depot. The drug depot will allow fluid in the depotto displace the drug. However, cell infiltration into the depot will beprevented by the size of the pores of the depot. In this way, in someembodiments, the depot should not function as a tissue scaffold andallow tissue growth. Rather, the drug depot will solely be utilized fordrug delivery. In some embodiments, the pores in the drug depot will beless than 250 to 500 microns. This pore size will prevent cells frominfiltrating the drug depot and laying down scaffolding cells. Thus, inthis embodiment, drug will elute from the drug depot as fluid enters thedrug depot, but cells will be prevented from entering. In someembodiments, where there are little or no pores, the drug will elute outfrom the drug depot by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body.

A “therapeutically effective amount” or “effective amount” is such thatwhen administered, the drug results in alteration of the biologicalactivity, such as, for example, inhibition of inflammation, reduction oralleviation of pain, improvement in the condition through inhibition ofan immunologic response, etc. The dosage administered to a patient canbe as single or multiple doses depending upon a variety of factors,including the drug's administered pharmacokinetic properties, the routeof administration, patient conditions and characteristics (sex, age,body weight, health, size, etc.), extent of symptoms, concurrenttreatments, frequency of treatment and the effect desired. In someembodiments the formulation is designed for immediate release. In otherembodiments the formulation is designed for sustained release. In otherembodiments, the formulation comprises one or more immediate releasesurfaces and one or more sustained release surfaces.

A “depot” includes but is not limited to capsules, microspheres,microparticles, microcapsules, microfibers particles, nanospheres,nanoparticles, coating, matrices, wafers, pills, pellets, emulsions,liposomes, micelles, gels, or other pharmaceutical delivery compositionsor a combination thereof. Suitable materials for the depot are ideallypharmaceutically acceptable biodegradable and/or any bioabsorbablematerials that are preferably FDA approved or GRAS materials. Thesematerials can be polymeric or non-polymeric, as well as synthetic ornaturally occurring, or a combination thereof.

The term “biodegradable” includes that all or parts of the drug depotwill degrade over time by the action of enzymes, by hydrolytic actionand/or by other similar mechanisms in the human body. In variousembodiments, “biodegradable” includes that the depot (e.g.,microparticle, microsphere, etc.) can break down or degrade within thebody to non-toxic components after or while a therapeutic agent has beenor is being released. By “bioerodible” it is meant that the depot willerode or degrade over time due, at least in part, to contact withsubstances found in the surrounding tissue, fluids or by cellularaction. By “bioabsorbable” it is meant that the depot will be brokendown and absorbed within the human body, for example, by a cell ortissue. “Biocompatible” means that the depot will not cause substantialtissue irritation or necrosis at the target tissue site.

The phrases “sustained release” and “sustain release” (also referred toas extended release or controlled release) are used herein to refer toone or more therapeutic agent(s) that is introduced into the body of ahuman or other mammal and continuously or continually releases a streamof one or more therapeutic agents over a predetermined time period andat a therapeutic level sufficient to achieve a desired therapeuticeffect throughout the predetermined time period. Reference to acontinuous or continual release stream is intended to encompass releasethat occurs as the result of biodegradation in vivo of the drug depot,or a matrix or component thereof, or as the result of metabolictransformation or dissolution of the therapeutic agent(s) or conjugatesof therapeutic agent(s).

The phrase “immediate release” is used herein to refer to one or moretherapeutic agent(s) that is introduced into the body and that isallowed to dissolve in or become absorbed at the location to which it isadministered, with no intention of delaying or prolonging thedissolution or absorption of the drug.

The phrase “undesirable macrophage activity” refers to the activity ofmacrophages that are destructive to an organism including theself-destructive activity of breaking down cartilage or bone. Theprevention or reduction of this undesirable macrophage activity may thushave either an osteoprotective or cartilage protective function. Forexample, through the methods and formulations, some embodiments mayprevent at least 10%, at least 20%, as least 30%, at least 40%, at least50%, at least 60%, at least 70%, at least 80%, at least 90% or at least100% of the break down of bone and/or cartilage that might otherwiseoccur in a patient in need of such treatment.

The two types of formulations (sustain release and immediate release)may be used in conjunction. For example, one can use a mixture offormulations that provide different release profiles, either by use ofdifferent forms of the drug or by mixtures of different formulations ofsustained release materials. The sustained release and immediate releasemay be in one or more of the same depots. In various embodiments, thesustained release and immediate release may be part of separate depots.For example a bolus or immediate release formulation of fluocinolone maybe placed at or near the target site and a sustain release formulationmay also be placed at or near the same site or be provided within thesame formulation through a combination of different polymer matricesand/or drug forms. Thus, even after the bolus becomes completelyaccessible, the sustain release formulation would continue to providethe active ingredient for the intended tissue.

In various embodiments, the drug depot can be designed to cause aninitial burst dose of therapeutic agent within the first twenty-fourhours after implantation. “Initial burst” or “burst effect” or “bolusdose” refers to the release of therapeutic agent from the depot duringthe first twenty-four hours after the depot comes in contact with anaqueous fluid (e.g., synovial fluid, cerebral spinal fluid, etc.). The“burst effect” is believed to be due to the increased release oftherapeutic agent from the depot. In alternative embodiments, the depot(e.g., gel) is designed to avoid this initial burst effect.

“Treating” or “treatment” of a disease or condition refers to executinga protocol that may include administering one or more drugs to a patient(human, other normal or otherwise or other mammal), in an effort toalleviate signs or symptoms of the disease or condition or immunologicalresponse. Alleviation can occur prior to signs or symptoms of thedisease or condition appearing, as well as after their appearance. Thus,treating or treatment includes preventing or prevention of disease orundesirable condition. In addition, treating, treatment, preventing orprevention do not require complete alleviation of signs or symptoms,does not require a cure, and specifically includes protocols that haveonly a marginal effect on the patient. Some conditions of pain and/orinflammation include chronic conditions, such as for example, rheumatoidarthritis, osteoarthritis, sciatica, carpal tunnel syndrome, lower backpain, lower extremity pain, upper extremity pain, cancer, tissue painand pain associated with injury or repair of cervical, thoracic, and/orlumbar vertebrae or intervertebral discs, rotator cuff, articular joint,TMJ, tendons, ligaments, muscles, tissue or organ transplant rejectionor the like. “Reducing inflammation” includes a decrease in inflammationand/or rejection and does not require complete alleviation of signs orsymptoms of inflammation or rejection, and does not require a cure. Invarious embodiments, reducing inflammation includes even a marginaldecrease in inflammation and/or issue or organ rejection.

The term “pain” includes nociception and the sensation of pain, both ofwhich can be assessed objectively and subjectively, using pain scoresand other methods well-known in the art. In various embodiments, painmay include allodynia (e.g., increased response to a normallynon-noxious stimulus) or hyperalgesia (e.g.,increased response to anormally noxious or unpleasant stimulus), which can in turn be thermalor mechanical (tactile) in nature. In some embodiments, pain ischaracterized by thermal sensitivity, mechanical sensitivity and/orresting pain. In other embodiments, pain comprises mechanically-inducedpain or resting pain. In still other embodiments, the pain comprisesresting pain. The pain can be primary or secondary pain, as iswell-known in the art. Exemplary types of pain reducible, preventable ortreatable by the methods and compositions disclosed herein include,without limitation, lower back pain, neck pain, leg pain, radicularpain, or abdominal pain from abdominal surgery, and neuropathic pain ofthe arm, neck, back, lower back, leg, and related pain distributionsresulting from disk or spine surgery.

“Localized” delivery includes delivery where one or more drugs aredeposited within a tissue, for example, at a nerve root of the nervoussystem or a region of the brain, or in close proximity (within about 10cm, or preferably within about 5 cm or preferably within about 0.1 cm,for example) thereto.

The term “mammal” refers to organisms from the taxonomy class“mammalian,” including but not limited to humans, other primates such aschimpanzees, apes, orangutans and monkeys, rats, mice, cats, dogs, cows,horses, etc.

The phrase “release rate profile” refers to the percentage of activeingredient that is released over fixed units of time, e.g., mcg/hr,mcg/day, 10% per day for ten days, etc. As persons of ordinary skillknow a release rate profile may, but need not, be linear.

The term “solid” is intended to mean a rigid material, while“semi-solid” is intended to mean a material that has some degree offlexibility, thereby allowing the depot to bend and conform to thesurrounding tissue requirements.

“Targeted delivery system” provides delivery of one or more drugsdepots, gels or depots dispersed in the gel having a quantity oftherapeutic agent that can be deposited at or near the target site asneeded.

The phrase “target site” refers to the site at which symptoms and/orcauses of a disorder occur, for example, it may be a site at whichmacrophages causes the destruction of cartilage at a joint.

The term “tissue” refers to any body tissue or organ from or within anorganism, including but not limited to pancreatic tissue, liver tissue,skin tissue, kidney tissue, heart tissue, etc.

The abbreviation “DLG” refers to poly(DL-lactide-co-glycolide).

The abbreviation “DL” refers to poly(DL-lactide).

The abbreviation “LG” refers to poly(L-lactide-co-glycolide).

The abbreviation “CL” refers to polycaprolactone.

The abbreviation “DLCL” refers to poly(DL-lactide-co-caprolactone).

The abbreviation “LCL” refers to poly(L-lactide-co-caprolactone).

The abbreviation “G” refers to polyglycolide.

The abbreviation “PEG” refers to poly(ethylene glycol).

The abbreviation “PLGA” refers to poly(lactide-co-glycolide).

The abbreviation “PLA” refers to polyglycolide.

The abbreviation “POE” refers to poly(orthoester)

The term “arthritis” refers to a group of conditions involving damage tothe joints of the body. There are different forms of arthritis; each hasa different cause. The most common form of arthritis is osteoarthitis,which is also known as degenerative joint disease, and is a result oftrauma to the joint, infection of the joint, or age. Other arthritisforms include but are not limited to rheumatoid arthritis, psoriaticarthritis, autoimmune diseases in which the body attackes itself, andgouty arthritis, which is caused by deposition of uric acid crystals inthe joint.

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdrawings. While the invention will be described in conjunction with theillustrated embodiments, it will be understood that they are notintended to limit the invention to those embodiments. On the contrary,the invention is intended to cover all alternatives, modifications, andequivalents that may be included within the invention as defined by theappended claims.

Fluocinolone

When referring to fluocinolone, unless otherwise specified or apparentfrom context it is understood that the inventors are also referring topharmaceutically acceptable salts. One common form of fluocinolone foradministration to mammals is fluocinolone acetonide. Examples ofpotentially pharmaceutically acceptable salts include those salt-formingacids and bases that do not substantially increase the toxicity of acompound, such as, salts of alkali metals such as magnesium, potassiumand ammonium, salts of mineral acids such as hydrochloric, hydriodic,hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, aswell as salts of organic acids such as tartaric, acetic, citric, malic,benzoic, glycollic, gluconic, gulonic, succinic, arylsulfonic, e.g.,p-toluenesulfonic acids, and the like.

Further, when referring to fluocinolone the active ingredient may notonly be in the salt form, but also in the base form (e.g., free base).In various embodiments, if it is in the base form, it may be combinedwith polymers under conditions in which there is not severe polymerdegradation, as may be seen upon heat or solvent processing that mayoccur with PLGA or PLA.

The fluocinolone or its pharmaceutically acceptable salt may beadministered with a muscle relaxant. Exemplary muscle relaxants includeby way of example and not limitation, alcuronium chloride, atracuriumbescylate, baclofen, carbamate, carbolonium, carisoprodol,chlorphenesin, chlorzoxazone, cyclobenzaprine, dantrolene, decamethoniumbromide, fazadinium, gallamine triethiodide, hexafluorenium,meladrazine, mephensin, metaxalone, methocarbamol, metocurine iodide,pancuronium, pridinol mesylate, styramate, suxamethonium, suxethonium,thiocolchicoside, tizanidine, tolperisone, tubocuarine, vecuronium, orcombinations thereof.

The drug depot may comprise other therapeutic agents in addition to thefluocinolone as well. These therapeutic agents, in various embodiments,block the transcription or translation of TNF-α or other proteins in theinflammation cascade. Suitable therapeutic agents include, but are notlimited to, integrin antagonists, alpha-4beta-7 integrin antagonists,cell adhesion inhibitors, interferon gamma antagonists, CTLA4-Igagonists/antagonists (BMS-188667), CD40 ligand antagonists, Humanizedanti-IL-6 mAb (MRA, Tocilizumab, Chugai), HMGB-1 mAb (CriticalTherapeutics Inc.), anti-IL2R antibodies (daclizumab, basilicimab), ABX(anti IL-8 antibodies), recombinant human IL-10, or HuMax IL-15 (anti-IL15 antibodies).

Other suitable therapeutic agents include IL-1 inhibitors, such Kineret®(anakinra) which is a recombinant, non-glycosylated form of the humaninerleukin-1 receptor antagonist (IL-1Ra), or AMG 108, which is amonoclonal antibody that blocks the action of IL-1. Therapeutic agentsalso include excitatory amino acids such as glutamate and aspartate,antagonists or inhibitors of glutamate binding to NMDA receptors, AMPAreceptors, and/or kainate receptors. Interleukin-1 receptor antagonists,thalidomide (a TNF-α release inhibitor), thalidomide analogues (whichreduce TNF-α production by macrophages), bone morphogenetic protein(BMP) type 2 and BMP-4 (inhibitors of caspase 8, a TNF-α activator),quinapril (an inhibitor of angiotensin II, which upregulates TNF-α),interferons such as IL-11 (which modulate TNF-α receptor expression),and aurin-tricarboxylic acid (which inhibits TNF-α), may also be usefulas therapeutic agents for reducing inflammation. It is furthercontemplated that where desirable a pegylated form of the above may beused. Examples of still other therapeutic agents include NF kappa Binhibitors such as antioxidants, such as dilhiocarbamate, and othercompounds, such as, for example, sulfasalazine.

Examples of therapeutic agents suitable for use also include, but arenot limited to an anti-inflammatory agent, analgesic agent, orosteoinductive growth factor or a combination thereof. Anti-inflammatoryagents include, but are not limited to, apazone, celecoxib, diclofenac,diflunisal, enolic acids (piroxicam, meloxicam), etodolac, fenamates(mefenamic acid, meclofenamic acid), gold, ibuprofen, indomethacin,ketoprofen, ketorolac, nabumetone, naproxen, nimesulide, salicylates,sulfasalazine [2-hydroxy-5-[-4-[C2-pyridinylamino)sulfonyl]azo]benzoicacid, sulindac, tepoxalin. or tolmetin; as well as antioxidants, such asdithiocarbamate, steroids, such as cortisol, cortisone, hydrocortisone,fludrocortisone, prednisone, prednisolone, methylprednisolone,triamcinolone, betamethasone, dexamethasone, beclomethasone, fluticasoneor a combination thereof.

Suitable anabolic growth or anti-catabolic growth factors include, butare not limited to, a bone morphogenetic protein, a growthdifferentiation factor, a LIM mineralization protein, CDMP or progenitorcells or a combination thereof.

Suitable analgesic agents include, but are not limited to,acetaminophen, alfentanil, amitriptyline, bupivicaine, lidocaine, opioidanalgesics such as buprenorphine, butorphanol, carbamazepine, codeine,dextromoramide, dextropropoxyphene, dezocine, dextropropoxyphene,diamorphine, dihydrocodeine, eptazocine, fentanyl, flupirtine,gabapentin hydrocodone, hydromorphone, ketobemidone, levomethadyl,mepiridine, methadone, meptazinol, morphine, nalbuphine, opium,oxycodone, papaveretum, pentazocine, pethidine, phenoperidine,piritramide, pregabalin, remifentanil, sufentanil, tilidine, tramadol,or a combination thereof.

The fluocinolone may also be administered with non-active ingredients.These non-active ingredients may have multi-functional purposesincluding the carrying, stabilizing and controlling the release of thetherapeutic agent(s). The sustained release process, for example, may beby a solution-diffusion mechanism or it may be governed by anerosion-sustained process. Typically, the depot will be a solid orsemi-solid formulation comprised of a biocompatible material that can bebiodegradable.

In various embodiments, the non-active ingredients will be durablewithin the tissue site for a period of time equal to (for biodegradablecomponents) or greater than (for non-biodegradable components) theplanned period of drug delivery. For example, the depot material mayhave a melting point or glass transition temperature close to or higherthan body temperature, but lower than the decomposition or degradationtemperature of the therapeutic agent. However, the pre-determinederosion of the depot material can also be used to provide for slowrelease of the loaded therapeutic agent(s). Non-biodegradable polymersinclude but are not limited to PVC and polyurethane.

In some embodiments, the drug depot may not be biodegradable. Forexample, the drug depot may comprise polyurethane, polyurea,polyether(amide), PEBA, thermoplastic elastomeric olefin, copolyester,and styrenic thermoplastic elastomer, steel, aluminum, stainless steel,titanium, metal alloys with high non-ferrous metal content and a lowrelative proportion of iron, carbon fiber, glass fiber, plastics,ceramics or combinations thereof. Typically, these types of drug depotsmay need to be removed after a certain amount of time.

In some instances, it may be desirable to avoid having to remove thedrug depot after use. In those instances, the depot may comprise abiodegradable material. There are numerous materials available for thispurpose and having the characteristic of being able to breakdown ordisintegrate over a prolonged period of time when positioned at or nearthe target tissue. As a function of the chemistry of the biodegradablematerial, the mechanism of the degradation process can be hydrolyticalor enzymatical in nature, or both. In various embodiments, thedegradation can occur either at the surface (heterogeneous or surfaceerosion) or uniformly throughout the drug delivery system depot(homogeneous or bulk erosion).

In various embodiments, the depot may comprise a bioerodable, abioabsorbable, and/or a biodegradable biopolymer that may provideimmediate release, or sustained release of the fluocinolone. Examples ofsuitable sustained release biopolymers include but are not limited topoly (alpha-hydroxy acids), poly (lactide-co-glycolide) (PLGA),polylactide (PLA), polyglycolide (PG), polyethylene glycol (PEG)conjugates of poly (alpha-hydroxy acids), polyorthoesters (POE),polyaspirins, polyphosphagenes, collagen, starch, pre-gelatinizedstarch, hyaluronic acid, chitosans, gelatin, alginates, albumin, fibrin,vitamin E analogs, such as alpha tocopheryl acetate, d-alpha tocopherylsuccinate, D,L-lactide, or L-lactide, ,-caprolactone, dextrans,vinylpyrrolidone, polyvinyl alcohol (PVA), PVA-g-PLGA, PEGT-PBTcopolymer (polyactive), methacrylates, poly(N-isopropylacrylamide),PEO-PPO-PEO (pluronics), PEO-PPO-PAA copolymers, PLGA-PEO-PLGA, PEG-PLG,PLA-PLGA, poloxamer 407, PEG-PLGA-PEG triblock copolymers, SAIB (sucroseacetate isobutyrate) or combinations thereof. As persons of ordinaryskill are aware, mPEG may be used as a plasticizer for PLGA, but otherpolymers/excipients may be used to achieve the same effect. mPEG impartsmalleability to the resulting formulations.

The depot may optionally contain inactive materials such as bufferingagents and pH adjusting agents such as potassium bicarbonate, potassiumcarbonate, potassium hydroxide, sodium acetate, sodium borate, sodiumbicarbonate, sodium carbonate, sodium hydroxide or sodium phosphate;degradation/release modifiers; drug release adjusting agents;emulsifiers; preservatives such as benzalkonium chloride, chlorobutanol,phenylmercuric acetate and phenylmercuric nitrate, sodium bisulfate,sodium bisulfite, sodium thiosulfate, thimerosal, methylparaben,polyvinyl alcohol and phenylethyl alcohol; solubility adjusting agents;stabilizers; and/or cohesion modifiers. If the depot is to be placed inthe spinal area, in various embodiments, the depot may comprise sterilepreservative free material.

Exemplary excipients include but are not limited to mPEG, D-Sorbital,maltodextran, cyclodextrin and combinations thereof. The excipients,when present may for example be present in an amount of from about 0.05wt. % to about 85 wt. %.

The depot can be different sizes, shapes and configurations. There areseveral factors that can be taken into consideration in determining thesize, shape and configuration of the drug depot. For example, both thesize and shape may allow for ease in positioning the drug depot at thetarget tissue site that is selected as the implantation or injectionsite. In addition, the shape and size of the system should be selectedso as to minimize or prevent the drug depot from moving afterimplantation or injection. In various embodiments, the drug depot can beshaped like a sphere, a cylinder such as a rod or fiber, a flat surfacesuch as a disc, film or sheet or the like. Flexibility may be aconsideration so as to facilitate placement of the drug depot. Invarious embodiments, the drug depot can be different sizes, for example,the drug depot may be a length of from about 0.5 mm to 5 mm and have adiameter of from about 0.01 to about 2 mm. In various embodiments, thedrug depot may have a layer thickness of from about 0.005 to 1.0 mm,such as, for example, from 0.05 to 0.75 mm.

Radiographic markers can be included on the drug depot to permit theuser to position the depot accurately into the target site of thepatient. These radiographic markers will also permit the user to trackmovement and degradation of the depot at the site over time. In thisembodiment, the user may accurately position the depot in the site usingany of the numerous diagnostic imaging procedures. Such diagnosticimaging procedures include, for example, X-ray imaging or fluoroscopy.Examples of such radiographic markers include, but are not limited to,barium, calcium phosphate, and/or metal beads or particles. In variousembodiments, the radiographic marker could be a spherical shape or aring around the depot.

Gel

In various embodiments, the fluocinolone is administered in a gel. Thegel may have a pre-dosed viscosity in the range of about 1 to about 500centipoise (cps), 1 to about 200 cps, or 1 to about 100 cps. After thegel is administered to the target site, the viscosity of the gel willincrease and the gel will have a modulus of elasticity (Young's modulus)in the range of about 1×10⁴ to about 6×10⁵ dynes/cm², or 2×10⁴ to about5×10⁵ dynes/cm², or 5×10⁴ to about 5×10⁵ dynes/cm².

In one embodiment, a depot comprises an adherent gel comprisingfluocinolone that is evenly distributed throughout the gel. The gel maybe of any suitable type, as previously indicated, and should besufficiently viscous so as to prevent the gel from migrating from thetargeted delivery site once deployed; the gel should, in effect, “stick”or adhere to the targeted tissue site. The gel may, for example,solidify upon contact with the targeted tissue or after deployment froma targeted delivery system. The targeted delivery system may be, forexample, a syringe, a catheter, needle or cannula or any other suitabledevice. The targeted delivery system may inject the gel into or on thetargeted tissue site. The therapeutic agent may be mixed into the gelprior to the gel being deployed at the targeted tissue site. In variousembodiments, the gel may be part of a two-component delivery system andwhen the two components are mixed, a chemical process is activated toform the gel and cause it to stick or to adhere to the target tissue.

In various embodiments, a gel is provided that hardens or stiffens afterdelivery. Typically, hardening gel formulations may have a pre-dosedmodulus of elasticity in the range of about 1×10⁴ to about 3×10⁵dynes/cm², or 2×10⁴ to about 2×10⁵ dynes/cm², or 5×10⁴ to about 1×10⁵dynes/cm². The post-dosed hardening gels (after delivery) may have arubbery consistency and have a modulus of elasticity in the range ofabout 1×10⁴ to about 2×10⁶ dynes/cm², or 1×10⁵ to about 7×10⁵ dynes/cm²,or 2×10⁵ to about 5×10⁵ dynes/cm². Other IV ranges include but are notlimited to about 0.05 to about 0.15 dL/g, about 0.10 to about 0.20 dL/g,about 0.15 to about 0.25 dL/g, about 0.20 to about 0.30 dL/g, about 0.25to about 0.35 dL/g, about 0.30 to about 0.35 dL/g, about 0.35 to about0.45 dL/g, about 0.40 to about 0.45 dL/g, about 0.45 to about 0.50 dL/g,about 0.50 to about 0.70 dL/g, about 0.60 to about 0.80 dL/g, about 0.70to about 0.90 dL/g, and about 0.80 to about 1.00 dL/g.

In various embodiments, for those gel formulations that contain apolymer, the polymer concentration may affect the rate at which the gelhardens (e.g., a gel with a higher concentration of polymer maycoagulate more quickly than gels having a lower concentration ofpolymer). In various embodiments, when the gel hardens, the resultingmatrix is solid but is also able to conform to the irregular surface ofthe tissue (e.g., recesses and/or projections in bone).

The percentage of polymer present in the gel may also affect theviscosity of the polymeric composition. For example, a compositionhaving a higher percentage by weight of polymer is typically thicker andmore viscous than a composition having a lower percentage by weight ofpolymer. A more viscous composition tends to flow more slowly.Therefore, a composition having a lower viscosity may be preferred insome instances. In some embodiments, the polymer comprises 20 wt. % to90 wt. % of the formulation.

In various embodiments, the molecular weight of the gel can be varied bymany methods known in the art. The molecular weight of the polymer canbe varied to regulate the release rate profile and/or delivery durationof the active ingredient. In general, as the molecular weight of thepolymer increases, one or more of the following occurs: the burst indexis lower, the release profile is flatter and/or the duration of deliveryis longer. The choice of method to vary molecular weight is typicallydetermined by the composition of the gel (e.g., polymer, versusnon-polymer). For example in various embodiments, when the gel comprisesone or more polymers, the degree of polymerization can be controlled byvarying the amount of polymer initiators (e.g. benzoyl peroxide),organic solvents or activator (e.g. DMPT), crosslinking agents,polymerization agent, and/or reaction time. By was of a non-limitingexample, the polymer make up may comprise from 50:50 PLGA to 100 PLA andthe molecular weight range may be from 0.45 to 0.8 dI/g.

Suitable gel polymers may be soluble in an organic solvent. Thesolubility of a polymer in a solvent varies depending on thecrystallinity, hydrophobicity, hydrogen-bonding and molecular weight ofthe polymer. Lower molecular weight polymers will normally dissolve morereadily in an organic solvent than high-molecular weight polymers. Apolymeric gel that includes a high molecular weight polymer tends tocoagulate or solidify more quickly than a polymeric composition, whichincludes a low-molecular weight polymer. Polymeric gel formulations thatinclude high molecular weight polymers, also tend to have a highersolution viscosity than a polymeric gel, which include a low-molecularweight polymer.

As persons of ordinary skill in the art are aware, implantableelastomeric depot compositions having a blend of polymers with differentend groups are used the resulting formulation will have a lower burstindex and a regulated duration of delivery. For example, one may usepolymers with acid (e.g., carboxylic acid) and ester end groups (e.g.,methyl of ethyl ester end groups).

Additionally, by varying the comonomer ratio of the various monomersthat form a polymer (e.g., the L/G/CL or G/CL ration for a givenpolymer) there will be a resulting depot composition having a regulatedburst index and duration of delivery. For example, a depot compositionhaving a polymer with a L/G ration of 50:50 has a short duration ofdelivery ranging from about two days to about one month; a depotcomposition having a polymer with a L/G ratio of 65:35 has a duration ofdelivery of about two months; a depot composition having a polymer witha L/G ratio of 75:25 or L/CL ratio of 75:25 has a duration of deliveryof about three months to about four months; a depot composition having apolymer ratio with a L/G ratio of 85:15 has a duration of delivery ofabout five months; a depot composition having a polymer with a L/CLratio of 25:75 or PLA has a duration of delivery greater than or equalto six months; a depot composition having a terpolymer of CL/G/L with Ggreater than 50% and L greater than 10% has a duration of delivery ofabout one month and a depot composition having a terpolymer of CL/G/Lwith G less than 50% and L less than 10% has a duration months up to sixmonths. In general, increasing the G content relative to the CL contentshortens the duration of delivery whereas increasing the CL contentrelative to the G content lengthens the duration of delivery.

Thus, depot compositions having a blend of polymers having differentmolecular weights, end groups and comonomer ratios can be used to createa depot formulation having a lower burst index and a regulated durationof delivery.

When the gel is designed to be a flowable gel, it can vary from lowviscosity, similar to that of water, to high viscosity, similar to thatof a paste, depending on the molecular weight and concentration of thepolymer used in the gel. The viscosity of the gel can be varied suchthat the polymeric composition can be applied to a patient's tissues byany convenient technique, for example, by brushing, dripping, injecting,or painting. Different viscosities of the gel will depend on thetechnique used to apply the composition.

In various embodiments, the gel has an inherent viscosity (abbreviatedas “I.V.” and units are in deciliters/gram), which is a measure of thegel's molecular weight and degradation time (e.g., a gel with a highinherent viscosity has a higher molecular weight and longer degradationtime). Typically, a gel with a high molecular weight provides a strongermatrix and the matrix takes more time to degrade. In contrast, a gelwith a low molecular weight degrades more quickly and provides a softermatrix. In various embodiments, the gel has a molecular weight, as shownby the inherent viscosity, from about 0.10 dL/g to about 1.2 dL/g orfrom about 0.10 dL/g to about 0.40 dL/g.

In various embodiments, the gel can have a viscosity of about 300 toabout 5,000 centipoise (cp). In other embodiments, the gel can have aviscosity of from about 5 to about 300 cps, from about 10 cps to about50 cps, from about 15 cps to about 75 cps at room temperature. The gelmay optionally have a viscosity enhancing agent such as, for example,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethylmethylcellulose, carboxymethylcellulose and salts thereof, Carbopol,poly-(hydroxyethylmethacrylate), poly-(methoxyethylmethacrylate),poly(methoxyethoxyethyl methacrylate), polymethylmethacrylate (PMMA),methylmethacrylate (MMA), gelatin, polyvinyl alcohols, propylene glycol,mPEG, PEG 200, PEG 300, PEG 400, PEG 500, PEG 600, PEG 700, PEG 800, PEG900, PEG 1000, PEG 1450, PEG 3350, PEG 4500, PEG 8000 or combinationsthereof.

In various embodiments, the gel is a hydrogel made of high molecularweight biocompatible elastomeric polymers of synthetic or naturalorigin. A desirable property for the hydrogel to have is the ability torespond rapidly to mechanical stresses, particularly shears and loads,in the human body.

Hydrogels obtained from natural sources are particularly appealingbecause they are more likely to be biodegradable and biocompatible forin vivo applications. Suitable hydrogels include natural hydrogels, suchas for example, gelatin, collagen, silk, elastin, fibrin andpolysaccharide-derived polymers like agarose, and chitosan, glucomannangel, hyaluronic acid, polysaccharides, such as cross-linkedcarboxyl-containing polysaccharides, or a combination thereof. Synthetichydrogels include, but are not limited to those formed from polyvinylalcohol, acrylamides such as polyacrylic acid and poly(acrylonitrile-acrylic acid), polyurethanes, polyethylene glycol (e.g.,PEG 3350, PEG 4500, PEG 8000), silicone, polyolefins such aspolyisobutylene and polyisoprene, copolymers of silicone andpolyurethane, neoprene, nitrile, vulcanized rubber,poly(N-vinyl-2-pyrrolidone), acrylates such as poly(2-hydroxy ethylmethacrylate) and copolymers of acrylates with N-vinyl pyrolidone,N-vinyl lactams, polyacrylonitrile or combinations thereof. The hydrogelmaterials may further be cross-linked to provide further strength asneeded. Examples of different types of polyurethanes includethermoplastic or thermoset polyurethanes, aliphatic or aromaticpolyurethanes, polyetherurethane, polycarbonate-urethane or siliconepolyether-urethane, or a combination thereof.

In various embodiments, rather than directly admixing the therapeuticagent into the gel, microspheres may be dispersed within the gel, themicrospheres being loaded with fluocinolone. In one embodiment, themicrospheres provide for a sustained release of the fluocinolone. In yetanother embodiment, the gel, which is biodegradable, prevents themicrospheres from releasing the fluocinolone; the microspheres thus donot release the fluocinolone until they have been released from the gel.For example, a gel may be deployed around a target tissue site (e.g., anerve root). Dispersed within the gel are a plurality of microspheresthat encapsulate the desired therapeutic agent. Certain of thesemicrospheres degrade once released from the gel, thus releasing thefluocinolone.

Microspheres, much like a fluid, may disperse relatively quickly,depending upon the surrounding tissue type, and hence disperse thefluocinolone. In some situations, this may be desirable; in others, itmay be more desirable to keep the fluocinolone tightly constrained to awell-defined target site. The present invention also contemplates theuse of adherent gels to so constrain dispersal of the therapeutic agent.These gels may be deployed, for example, in a disc space, in a spinalcanal, or in surrounding tissue.

Drug Delivery

It will be appreciated by those with skill in the art that the depot canbe administered to the target site using a “cannula” or “needle” thatcan be a part of a drug delivery device e.g., a syringe, a gun drugdelivery device, or any medical device suitable for the application of adrug to a targeted organ or anatomic region. The cannula or needle ofthe drug depot device is designed to cause minimal physical andpsychological trauma to the patient.

Cannulas or needles include tubes that may be made from materials, suchas for example, polyurethane, polyurea, polyether(amide), PEBA,thermoplastic elastomeric olefin, copolyester, and styrenicthermoplastic elastomer, steel, aluminum, stainless steel, titanium,metal alloys with high non-ferrous metal content and a low relativeproportion of iron, carbon fiber, glass fiber, plastics, ceramics orcombinations thereof. The cannula or needle may optionally include oneor more tapered regions. In various embodiments, the cannula or needlemay be beveled. The cannula or needle may also have a tip style vitalfor accurate treatment of the patient depending on the site forimplantation. Examples of tip styles include, for example, Trephine,Cournand, Veress, Huber, Seldinger, Chiba, Francine, Bias, Crawford,deflected tips, Hustead, Lancet, or Tuohey. In various embodiments, thecannula or needle may also be non-coring and have a sheath covering itto avoid unwanted needle sticks.

The dimensions of the hollow cannula or needle, among other things, willdepend on the site for implantation. For example, the width of theepidural space is only about 3-5 mm for the thoracic region and about5-7 mm for the lumbar region. Thus, the needle or cannula, in variousembodiments, can be designed for these specific areas. In variousembodiments, the cannula or needle may be inserted using atransforaminal approach in the spinal foramen space, for example, alongan inflammed nerve root and the drug depot implanted at this site fortreating the condition. Typically, the transforaminal approach involvesapproaching the intervertebral space through the intervertebralforamina.

Some examples of lengths of the cannula or needle may include, but arenot limited to, from about 50 to 150 mm in length, for example, about 65mm for epidural pediatric use, about 85 mm for a standard adult andabout 110 mm for an obese adult patient. The thickness of the cannula orneedle will also depend on the site of implantation. In variousembodiments, the thickness includes, but is not limited to, from about0.05 to about 1.655. The gauge of the cannula or needle may be thewidest or smallest diameter or a diameter in between for insertion intoa human or animal body. The widest diameter is typically about 14 gauge,while the smallest diameter is about 25 gauge. In various embodimentsthe gauge of the needle or cannula is about 18 to about 22 gauge.

In various embodiments, like the drug depot and/or gel, the cannula orneedle includes dose radiographic markers that indicate location at ornear the site beneath the skin, so that the user may accurately positionthe depot at or near the site using any of the numerous diagnosticimaging procedures. Such diagnostic imaging procedures include, forexample, X-ray imaging or fluoroscopy. Examples of such radiographicmarkers include, but are not limited to, barium, calcium, and/or metalbeads or particles.

In various embodiments, the needle or cannula may include a transparentor translucent portion that can be visualizable by ultrasound,fluoroscopy, X-ray, or other imaging techniques. In such embodiments,the transparent or translucent portion may include a radiopaque materialor ultrasound responsive topography that increases the contrast of theneedle or cannula relative to the absence of the material or topography.

The drug depot, and/or medical device to administer the drug may besterilizable. In various embodiments, one or more components of the drugdepot, and/or medical device to administer the drug are sterilized byradiation in a terminal sterilization step in the final packaging.Terminal sterilization of a product provides greater assurance ofsterility than from processes such as an aseptic process, which requireindividual product components to be sterilized separately and the finalpackage assembled in a sterile environment.

Typically, in various embodiments, gamma radiation is used in theterminal sterilization step, which involves utilizing ionizing energyfrom gamma rays that penetrates deeply in the device. Gamma rays arehighly effective in killing microorganisms. They leave no residues anddo not have sufficient energy to impart radioactivity to the device.Gamma rays can be employed when the device is in the package and gammasterilization does not require high pressures or vacuum conditions,thus, package seals and other components are not stressed. In addition,gamma radiation eliminates the need for permeable packaging materials.

In various embodiments, electron beam (e-beam) radiation may be used tosterilize one or more components of the device. E-beam radiationcomprises a form of ionizing energy, which is generally characterized bylow penetration and high-dose rates. E-beam irradiation is similar togamma processing in that it alters various chemical and molecular bondson contact, including the reproductive cells of microorganisms. Beamsproduced for e-beam sterilization are concentrated, highly-chargedstreams of electrons generated by the acceleration and conversion ofelectricity. E-beam sterilization may be used, for example, when thedrug depot is included in a gel.

Other methods may also be used to sterilize the depot and/or one or morecomponents of the device, including, but not limited to, gassterilization, such as, for example, with ethylene oxide or steamsterilization.

In various embodiments, a kit is provided that may include additionalparts along with the drug depot and/or medical device combined togetherto be used to implant the drug depot. The kit may include the drug depotdevice in a first compartment. The second compartment may include acanister holding the drug depot and any other instruments needed for thelocalized drug delivery. A third compartment may include gloves, drapes,wound dressings and other procedural supplies for maintaining sterilityof the implanting process, as well as an instruction booklet. A fourthcompartment may include additional cannulas and/or needles. A fifthcompartment may comprise an agent for radiographic imaging. Each toolmay be separately packaged in a plastic pouch that is radiationsterilized. A cover of the kit may include illustrations of theimplanting procedure and a clear plastic cover may be placed over thecompartments to maintain sterility.

In various embodiments, a method for delivering a therapeutic agent intoa site of a patient is provided, the method comprising inserting acannula at or near a target tissue site and implanting the drug depot atthe target site beneath the skin of the patient and brushing, dripping,injecting, or painting the gel in the target site to hold or have thedrug depot adhere to the target site. In this way unwanted migration ofthe drug depot away from the target site is reduced or eliminated.

In various embodiments, to administer the gel having the drug depotdispersed therein to the desired site, first the cannula or needle canbe inserted through the skin and soft tissue down to the target tissuesite and the gel administered at or near the target site. In thoseembodiments where the drug depot is separate from the gel, first thecannula or needle can be inserted through the skin and soft tissue downto the site of injection and one or more base layer(s) of gel can beadministered to the target site. Following administration of the one ormore base layer(s), the drug depot can be implanted on or in the baselayer(s) so that the gel can hold the depot in place or reducemigration. If required, a subsequent layer or layers of gel can beapplied on the drug depot to surround the depot and further hold it inplace. Alternatively, the drug depot may be implanted first and then thegel placed around the drug depot to hold it in place. By using the gel,accurate and precise implantation of a drug depot can be accomplishedwith minimal physical and psychological trauma to the patient. The gelalso avoids the need to suture the drug depot to the target sitereducing physical and psychological trauma to the patient.

In various embodiments, when the target site comprises a spinal region,a portion of fluid (e.g., spinal fluid, etc.) can be withdrawn from thetarget site through the cannula or needle first and then the depotadministered (e.g., placed, dripped, injected, or implanted, etc.). Thetarget site will re-hydrate (e.g., replenishment of fluid) and thisaqueous environment will cause the drug to be released from the depot.

Although the spinal site is described above, the drug depot can bedelivered to any site beneath the skin, including, but not limited to,at least one muscle, ligament, tendon, cartilage, spinal disc, spinalforaminal space, near the spinal nerve root, or spinal canal. The drugdepot may also be administered locally to any site at which there isundesirable macrophage activity, including but not limited to arthriticsite such as the joints of the hand, finger, wrist, elbow, shoulder,knee, ankle hip, foot, toe, pelvis and neck.

The fluocinolone-based formulation of the present application may beused as medicaments in the form of pharmaceutical preparations. Thepreparations may be formed in an administration with a suitablepharmaceutical carrier that may be solid or liquid and organic orinorganic, and placed in the appropriate form for parenteral or otheradministration as desired. As persons of ordinary skill are aware, knowncarriers include but are not limited to water, gelatine, lactose,starches, stearic acid, magnesium stearate, sicaryl alcohol, talc,vegetable oils, benzyl alcohols, gums, waxes, propylene glycol,polyalkylene glycols and other known carriers for medicaments.

Parenteral administration may additionally include, for example, aninfusion pump that administers a pharmaceutical composition through acatheter, an implantable mini-pump that can be inserted at or near thetarget site, an implantable controlled release device or sustainedrelease delivery system that can release a certain amount of thecomposition per hour or in intermittent bolus doses. One example of asuitable pump for use is the SynchroMed® (Medtronic, Minneapolis, Minn.)pump. This pump has three sealed chambers. One contains an electronicmodule and battery. The second contains a peristaltic pump and drugreservoir. The third contains an inert gas, which provides the pressureneeded to force the pharmaceutical composition into the peristalticpump. To fill the pump, the pharmaceutical composition is injectedthrough the reservoir fill port to the expandable reservoir. The inertgas creates pressure on the reservoir, and the pressure forces thepharmaceutical composition through a filter and into the pump chamber.The pharmaceutical composition is then pumped out of the device from thepump chamber and into the catheter, which will direct it for deposit atthe target site. The rate of delivery of pharmaceutical composition iscontrolled by a microprocessor. This allows the pump to be used todeliver similar or different amounts of pharmaceutical compositioncontinuously, at specific times, or at set intervals between deliveries.

Another embodiment of the present invention is directed to a method fortreating a mammal that has received a tissue transplant, said methodcomprising administering a therapeutically effective amount offluocinolone at a target site beneath the skin. The fluocinolone (orpharmaceutically acceptable salt) may for example be administeredlocally to the target tissue site as a drug depot.

In some embodiments, the fluocinolone is encapsulated in a plurality ofdepots comprising microparticles, microspheres, microcapsules, and/ormicrofibers.

In some embodiments there is a method for making an implantable drugdepot. The method may comprise combining a biocompatible polymer and atherapeutically effective amount of fluocinolone or a pharmaceuticallyacceptable salt thereof and forming the implantable drug depot from thecombination.

In some embodiments, the fluocinolone is suitable for parenteraladministration. The term “parenteral” as used herein refers to modes ofadministration that bypass the gastrointestinal tract, and include forexample, intravenous, intramuscular, continuous or intermittentinfusion, intraperitoneal, intrasternal, subcutaneous,intra-operatively, intrathecally, intradiskally, peridiskally,epidurally, perispinally, intraarticular injection or combinationsthereof. In some embodiments, the injection is intrathecal, which refersto an injection into the spinal canal (intrathecal space surrounding thespinal cord). An injection may also be into a muscle or other tissue.

In various embodiments, the drug depot comprising the fluocinolone canbe made by combining a biocompatible polymer and a therapeuticallyeffective amount of fluocinolone or pharmaceutically acceptable saltthereof and forming the implantable drug depot from the combination.

Various techniques are available for forming at least a portion of adrug depot from the biocompatible polymer(s), therapeutic agent(s), andoptional materials, including solution processing techniques and/orthermoplastic processing techniques. Where solution processingtechniques are used, a solvent system is typically selected thatcontains one or more solvent species. The solvent system is generally agood solvent for at least one component of interest, for example,biocompatible polymer and/or therapeutic agent. The particular solventspecies that make up the solvent system can also be selected based onother characteristics, including drying rate and surface tension.

Solution processing techniques include solvent casting techniques, spincoating techniques, web coating techniques, solvent spraying techniques,dipping techniques, techniques involving coating via mechanicalsuspension, including air suspension (e.g., fluidized coating), ink jettechniques and electrostatic techniques. Where appropriate, techniquessuch as those listed above can be repeated or combined to build up thedepot to obtain the desired release rate and desired thickness.

In various embodiments, a solution containing solvent and biocompatiblepolymer are combined and placed in a mold of the desired size and shape.In this way, polymeric regions, including barrier layers, lubriciouslayers, and so forth can be formed. If desired, the solution can furthercomprise, one or more of the following: fluocinolone and othertherapeutic agent(s) and other optional additives such as radiographicagent(s), etc. in dissolved or dispersed form. This results in apolymeric matrix region containing these species after solvent removal.In other embodiments, a solution containing solvent with dissolved ordispersed therapeutic agent is applied to a pre-existing polymericregion, which can be formed using a variety of techniques includingsolution processing and thermoplastic processing techniques, whereuponthe therapeutic agent is imbibed into the polymeric region.

Thermoplastic processing techniques for forming the depot or portionsthereof include molding techniques (for example, injection molding,rotational molding, and so forth), extrusion techniques (for example,extrusion, co-extrusion, multi-layer extrusion, and so forth) andcasting.

Thermoplastic processing in accordance with various embodimentscomprises mixing or compounding, in one or more stages, thebiocompatible polymer(s) and one or more of the following: fluocinolone,optional additional therapeutic agent(s), radiographic agent(s), and soforth. The resulting mixture is then shaped into an implantable drugdepot. The mixing and shaping operations may be performed using any ofthe conventional devices known in the art for such purposes.

During thermoplastic processing, there exists the potential for thetherapeutic agent(s) to degrade, for example, due to elevatedtemperatures and/or mechanical shear that are associated with suchprocessing. For example, fluocinolone may undergo substantialdegradation under ordinary thermoplastic processing conditions. Hence,processing is preferably performed under modified conditions, whichprevent the substantial degradation of the therapeutic agent(s).Although it is understood that some degradation may be unavoidableduring thermoplastic processing, degradation is generally limited to 10%or less. Among the processing conditions that may be controlled duringprocessing to avoid substantial degradation of the therapeutic agent(s)are temperature, applied shear rate, applied shear stress, residencetime of the mixture containing the therapeutic agent, and the techniqueby which the polymeric material and the therapeutic agent(s) are mixed.

Mixing or compounding biocompatible polymer with therapeutic agent(s)and any additional additives to form a substantially homogenous mixturethereof may be performed with any device known in the art andconventionally used for mixing polymeric materials with additives.

Where thermoplastic materials are employed, a polymer melt may be formedby heating the biocompatible polymer, which can be mixed with variousadditives (e.g., therapeutic agent(s), inactive ingredients, etc.) toform a mixture. A common way of doing so is to apply mechanical shear toa mixture of the biocompatible polymer(s) and additive(s). Devices inwhich the biocompatible polymer(s) and additive(s) may be mixed in thisfashion include devices such as single screw extruders, twin screwextruders, banbury mixers, high-speed mixers, ross kettles, and soforth.

Any of the biocompatible polymer(s) and various additives may bepremixed prior to a final thermoplastic mixing and shaping process, ifdesired (e.g., to prevent substantial degradation of the therapeuticagent among other reasons).

For example, in various embodiments, a biocompatible polymer isprecompounded with a radiographic agent (e.g., radio-opacifying agent)under conditions of temperature and mechanical shear that would resultin substantial degradation of the therapeutic agent, if it were present.This precompounded material is then mixed with therapeutic agent underconditions of lower temperature and mechanical shear, and the resultingmixture is shaped into the fluocinolone containing drug depot.Conversely, in another embodiment, the biocompatible polymer can beprecompounded with the therapeutic agent under conditions of reducedtemperature and mechanical shear. This precompounded material is thenmixed with, for example, a radio-opacifying agent, also under conditionsof reduced temperature and mechanical shear, and the resulting mixtureis shaped into the drug depot.

The conditions used to achieve a mixture of the biocompatible polymerand therapeutic agent and other additives will depend on a number offactors including, for example, the specific biocompatible polymer(s)and additive(s) used, as well as the type of mixing device used.

As an example, different biocompatible polymers will typically soften tofacilitate mixing at different temperatures. For instance, where a depotis formed comprising PLGA or PLA polymer, a radio-opacifying agent(e.g., bismuth subcarbonate), and a therapeutic agent prone todegradation by heat and/or mechanical shear (e.g., fluocinolone), invarious embodiments, the PGLA or PLA can be premixed with theradio-opacifying agent at temperatures of about, for example, 150° C. to170° C. The therapeutic agent is then combined with the premixedcomposition and subjected to further thermoplastic processing atconditions of temperature and mechanical shear that are substantiallylower than is typical for PGLA or PLA compositions. For example, whereextruders are used, barrel temperature, volumetric output are typicallycontrolled to limit the shear and therefore to prevent substantialdegradation of the therapeutic agent(s). For instance, the therapeuticagent and premixed composition can be mixed/compounded using a twinscrew extruder at substantially lower temperatures (e.g., 100-105° C.),and using substantially reduced volumetric output (e.g., less than 30%of full capacity, which generally corresponds to a volumetric output ofless than 200 cc/min). It is noted that this processing temperature iswell below the melting points of fluocinolone because processing at orabove these temperatures will result in substantial therapeutic agentdegradation. It is further noted that in certain embodiments, theprocessing temperature will be below the melting point of all bioactivecompounds within the composition, including the therapeutic agent. Aftercompounding, the resulting depot is shaped into the desired form, alsounder conditions of reduced temperature and shear.

In other embodiments, biodegradable polymer(s) and one or moretherapeutic agents are premixed using non-thermoplastic techniques. Forexample, the biocompatible polymer can be dissolved in a solvent systemcontaining one or more solvent species. Any desired agents (for example,a radio-opacifying agent, a therapeutic agent, or both radio-opacifyingagent and therapeutic agent) can also be dissolved or dispersed in thesolvents system. Solvent is then removed from the resultingsolution/dispersion, forming a solid material. The resulting solidmaterial can then be granulated for further thermoplastic processing(for example, extrusion) if desired.

As another example, the therapeutic agent can be dissolved or dispersedin a solvent system, which is then applied to a pre-existing drug depot(the pre-existing drug depot can be formed using a variety of techniquesincluding solution and thermoplastic processing techniques, and it cancomprise a variety of additives including a radio-opacifying agentand/or viscosity enhancing agent), whereupon the therapeutic agent isimbibed on or in the drug depot. As above, the resulting solid materialcan then be granulated for further processing, if desired.

Typically, an extrusion process may be used to form the drug depotcomprising a biocompatible polymer(s), therapeutic agent(s) andradio-opacifying agent(s). Co-extrusion may also be employed, which is ashaping process that can be used to produce a drug depot comprising thesame or different layers or regions (for example, a structure comprisingone or more polymeric matrix layers or regions that have permeability tofluids to allow immediate and/or sustained drug release). Multi-regiondepots can also be formed by other processing and shaping techniquessuch as co-injection or sequential injection molding technology.

In various embodiments, the depot that may emerge from the thermoplasticprocessing (e.g., pellet) is cooled. Examples of cooling processesinclude air cooling and/or immersion in a cooling bath. In someembodiments, a water bath is used to cool the extruded depot. However,where a water-soluble therapeutic agent such as fluocinolone is used,the immersion time should be held to a minimum to avoid unnecessary lossof therapeutic agent into the bath.

In various embodiments, immediate removal of water or moisture by use ofambient or warm air jets after exiting the bath will also preventre-crystallization of the drug on the depot surface, thus controlling orminimizing a high drug dose “initial burst” or “bolus dose” uponimplantation or insertion if this is release profile is not desired.

In various embodiments, the drug depot can be prepared by mixing orspraying the drug with the polymer and then molding the depot to thedesired shape. In various embodiments, fluocinolone is used and mixed orsprayed with the PLGA or PEG550 polymer, and the resulting depot may beformed by extrusion and dried.

In various embodiments, there is a pharmaceutical formulationcomprising: fluocinolone, wherein the fluocinolone comprises from about0.05 wt. % to about 25 wt. % of the formulation, and at least onebiodegradable polymer. In some embodiments, the pharmaceutical thefluocinolone comprises from about 3 wt. % to about 20 wt. %, about 3 wt.% to about 18 wt. %, about 5 wt. % to about 15 wt. % or about 7.5 wt. %to about 12.5 wt. % of the formulation.

In some embodiments, the at least one biodegradable polymer comprisespoly(lactic-co-glycolic acid) (PLA) or poly(orthoester) (POE) or acombination thereof. The poly(lactic-co-glycolic acid) may comprise amixture of polyglycolide (PGA) and polylactide and in some embodiments,in the mixture, there is more polylactide than polyglycolide. In variousembodiments there is 100% polylactide and 0% polyglycolide; 95%polylactide and 5% polyglycolide; 90% polylactide and 10% polyglycolide;85% polylactide and 15% polyglycolide; 80% polylactide and 20%polyglycolide; 75% polylactide and 25% polyglycolide; 70% polylactideand 30% polyglycolide; 65% polylactide and 35% polyglycolide; 60%polylactide and 40% polyglycolide; 55% polylactide and 45%polyglycolide; 50% polylactide and 50% polyglycolide; 45% polylactideand 55% polyglycolide; 40% polylactide and 60% polyglycolide; 35%polylactide and 65% polyglycolide; 30% polylactide and 70%polyglycolide; 25% polylactide and 75% polyglycolide; 20% polylactideand 80% polyglycolide; 15% polylactide and 85% polyglycolide; 10%polylactide and 90% polyglycolide; 5% polylactide and 95% polyglycolide;and 0% polylactide and 100% polyglycolide.

In various embodiments that comprise both polylactide and polyglycolide;there is at least 95% polylactide; at least 90% polylactide; at least85% polylactide; at least 80% polylactide; at least 75% polylactide; atleast 70% polylactide; at least 65% polylactide; at least 60%polylactide; at least 55%; at least 50% polylactide; at least 45%polylactide; at least 40% polylactide; at least 35% polylactide; atleast 30% polylactide; at least 25% polylactide; at least 20%polylactide; at least 15% polylactide; at least 10% polylactide; or atleast 5% polylactide; and the remainder of the biopolymer ispolyglycolide.

In some embodiments, the biodegradable polymer comprises at least 50 wt.% of the formulation, at least about 60 wt. % of the formulation, atleast about 70 wt. % of the formulation, at least 80 wt. % of theformulation, at least 85 wt. % of the formulation, at least 90 wt. % ofthe formulation, at least 95 wt. % of the formulation or at least 97 wt.% of the formulation. In some embodiments, the at least onebiodegradable polymer and the fluocinolone are the only components ofthe pharmaceutical formulation.

In some embodiments, at least 75% of the particles have a size fromabout 1 micrometer to about 30 micrometers. In some embodiments, atleast 85% of the particles have a size from about 1 micrometer to about30 micrometers. In some embodiments, at least 95% of the particles havea size from about 1 micrometer to about 30 micrometers. In someembodiments, all of the particles have a size from about 1 micrometer toabout 30 micrometers.

In some embodiments, at least 75% of the particles have a size fromabout 5 micrometer to about 20 micrometers. In some embodiments, atleast 85% of the particles have a size from about 5 micrometers to about20 micrometers. In some embodiments, at least 95% of the particles havea size from about 5 micrometer to about 20 micrometers. In someembodiments, all of the particles have a size from about 5 micrometer toabout 20 micrometers.

In some embodiments, there is a pharmaceutical formulation comprising:fluocinolone, wherein said fluocinolone comprises from about 0.05 wt. %to about 25 wt. % of the formulation, and at least one biodegradablepolymer, wherein the at least one biodegradable polymer comprisespoly(lactic-co-glycolic acid) or poly(orthoester) or a combinationthereof, and said at least one biodegradable polymer comprises at least80 wt. % of said formulation.

In some embodiments, there are methods for treating arthriticconditions, including but not limited to rheumatoid arthritis, psoriaticarthritis, osteoarthritis and pathogen-induced arthritic conditions, forexample, Lyme disease arthritis, bacterially induced arthritis, andpolioarthritis. These methods comprise: administering a pharmaceuticalcomposition to an organism, wherein said pharmaceutical compositioncomprises from about 0.05 wt. % to about 25 wt. % of the formulation,and at least one biodegradable polymer. In some embodiments, the loadingis from about 5 wt. % to about 10 wt. %. In some embodiments, theloading is from about 10 wt. % to about 20 wt. %.

In some embodiment there is a higher loading of fluocinolone, e.g., atleast 20 wt. %, at least 30 wt. %, at least 40 wt. %, at least 50 wt. %,at least 60 wt. %, at least 70 wt. %, at least 80 wt. %, or at least 90wt. %.

A strategy of triangulation may be effective when administering thesepharmaceutical formulations. Thus, a plurality (at least two, at leastthree, at least four, at least five, at least six, at least seven, etc.)drug depots comprising the pharmaceutical formulations may be placedaround the target tissue site such that the target tissue site fallswithin a region that is either between the formulations when there aretwo, or within an area whose perimeter is defined by a set of pluralityof formulations.

In some embodiments, the formulations are slightly rigid with varyinglength, widths, diameters, etc. For example, certain formulations mayhave a diameter of 0.75 mm and a length of 3 mm. It should be noted thatparticle size may be altered by techniques such as mortar and pestel,jet-drying or jet milling.

Fluocinolone is available from various pharmaceutical manufacturers. Thedosage of fluocinolone may be from approximately 0.0005 to approximately100 μg/day. Additional dosages of fluocinolone include fromapproximately 0.0005 to approximately 50 μg/day; approximately 0.0005 toapproximately 25 pg/day; approximately 0.0005 to approximately 10μg/day; approximately 0.0005 to approximately 5 μg/day; approximately0.0005 to approximately 1 μg/day; approximately 0.005 to approximately0.75 μg/day; approximately 0.0005 to approximately 0.5 μg/day;approximately 0.0005 to approximately 0.25 μg/day; approximately 0.0005to approximately 0.1 μg/day; approximately 0.0005 to approximately 0.075μg/day; approximately 0.0005 to approximately 0.05 μg/day; approximately0.001 to approximately 0.025 μg/day; approximately 0.001 toapproximately 0.01 μg/day; approximately 0.001 to approximately 0.0075μg/day; approximately 0.001 to approximately 0.005 μg/day; approximately0.001 to approximately 0.025 μg/day; and 0.002 to approximately 0.025μg/day. In another embodiment, the dosage of fluocinolone is fromapproximately 0.001 to approximately 15 μg/day. In another embodiment,the dosage of fluocinolone is from approximately 0.001 to approximately10 μg/day. In another embodiment, the dosage of fluocinolone is fromapproximately 0.001 to approximately 5 μg/day. In another embodiment,the dosage of fluocinolone is from approximately 0.001 to 2.5 μg/day. Insome embodiments, the amount of fluocinolone is between 40 and 600μg/day. In some embodiments, the amount of fluocinolone is between 200and 400 μg/day. Dosing formulations may be prepared to contain asufficient amount of the active ingredient to enable the desired aboutof compound to be release over the desired amount of time.

In some embodiments, there is sufficient fluocinolone such that thefluocinolone is released at a rate of 2-3 μg per day for a period of atleast three days. In some embodiments, this release rate continues for,at least ten days, at least fifteen days, at least twenty-five days, atleast thirty days, at least fifty days, at least ninety days, at leastone hundred days, at least one-hundred and thirty-five days, at leastone-hundred and fifty days, or at least one hundred and eighty days.

For some embodiments, 300-350 micrograms of fluocinolone as formulatedwith a biopolymer are implanted into a person at or near a target tissuesite. In some embodiments, the 300 micrograms to about 325 micrograms offluocinolone as formulated with a biopolymer are implanted into a personat or near a target tissue site. In some embodiments, the 325 microgramsto about 350 micrograms of fluocinolone as formulated with a biopolymerare implanted into a person at or near a target tissue site. Iffluocinolone is implanted at multiple sites that triangulate the targetsite then in some embodiments, the total amount of fluocinolone at eachsite is a fraction of the total 300-350 micrograms. For example, one mayimplant a single does of 324 micrograms at one site, or two separatedoses of 162 micrograms at two sites, or three separate dose of 108micrograms at three sites that triangulate the tissue site. It isimportant to limit the total dosage to an amount less than that whichwould be harmful to the organism. However, in some embodiments, althoughwhen there are a plurality of sites each site may contain less than thetotal does that might have been administered in a single application, itis important to remember that each site will independent have a releaseprofile, and the biopolymers' concentration and substance should beadjusted accordingly to ensure that the sustain release occurs oversufficient time.

In some embodiments, there is a drug depot comprising fluocinolone orfluocinolone and a polymer, wherein the polymer is one more ofpoly(lactide-co-glycolide) (PLGA), D-lactide, D,L-lactide, L-lactide,D,L-lactide-caprolactone, and D,L-lactide-glycolide-caprolactone.

The present invention may be used to target any undesirable macrophageactivity, including but not limited to the site the rheumatoid arthritisor osteoarthritis.

When developing formulations it in important to balance the limitedspace in which the activity can take place, with the goal of an extendedrelease period that may for example, be between 30 and 90 days, between30 and 40 days, between 40 and 50 days, between 50 and 60 days, between60 and 70 days, between 70 and 80 days or between 80 and 90 days. Asufficient amount of fluocinolone should be present in order to releasetherapeutic amounts over the desired time period.

Exemplary pellets may comprise fluocinolone and PLGA and be 0.5 to 1.5mm long and 0.5 to 1.0 mm in diameter. In some embodiments, at least oneor exactly one, at least two or exactly two, at least three or exactlythree pellets are placed less than about 2.0 cm, less than about 1.5 cm,less than about 1.0 cm or less than about 0.5 cm from the site ofinterest.

Additionally, in some embodiments it may be desirable to combine thefluocinolone with additional anti-inflammatory compounds, analgesics,anti-microbial compounds or combinations thereof.

When administering the drug depots, it may be advantageous for the drugdepots to be in the form of pellets that are injected in a formulationthat can adhere to the desired location, for example the joints of thehand, foot, fingers, toes, knees, elbows or shoulders.

Having now generally described the invention, the same may be morereadily understood through the following reference to the followingexample, which is provided by way of illustration and are not intendedto limit the present invention unless specified.

EXAMPLES Example 1

Summary: Fluocinolone-eluting pellets were evaluated for their abilityto modify the resorption and inflammatory response to subcutaneouslyimplanted inter-vertebral disc material [nucleus pulposus (NP)] in threegroups of five young female Sprague-Dawley rats three days after NPimplantation. The greatest resorption and least inflammatory responsewas observed in Group 1 (fluocinolone pellet in same pocket as NP) basedon both residual NP weight (n=4) and histological evaluation (n=l).Although not as pronounced as Group 1, treatment Group 2 in which thefluocinolone pellet was placed 1.5 cm from the NP implant also hasincreased resorption as compared to Group 3, the control pellettreatment group.

Objective: The objective of the study was to evaluate the effect offluocinolone-releasing pellets or control pellets on the resorption rateof subcutaneously implanted donor nucleus pulposus (NP) inter-vertebraldisc material.

Materials and Methods: The NP was removed from a total of eight discsfrom each of fifteen donor female Sprague-Dawley rats. The collected NPfrom each rat was pooled, weighed, and placed in a subcutaneousabdominal pocket of a single recipient female, Sprague-Dawley rat. Thefifteen recipient rats were randomly assigned to treatment groups offive animals each as described in the table below. Group 1 received afluocinolone-eluting pellet in the same subcutaneous pocket as the NPmaterial and had a surgical empty shame pocket created 1.5 cm away.Group 2 received NP material in a subcutaneous pocket and had afluocinolone-eluting pellet placed in a subcutaneous pocket 1.5 cm away.Group 3 received NP material in a subcutaneous pocket and had a controlpellet with no test article placed in a subcutaneous pocket 1.5 cm away.

TG Implant Location of Implant N 1 Fluocinolone-eluting Same pocket asNP 5 + 5* PLGA pellet (FLU-0 cm) + empty sham pocket 1.5 cm away 2Fluocinolone-eluting Separate pocket 5 + 5* PLGA pellet from NP, 1.5 cmaway (FLU-1.5 cm) 3 Control pellet Separate pocket 5 + 5* from NP, 1.5cm away (FLU-1.5 cm) *Second groups were donor animals that were usedfor NP collection.

Three days post surgery, animals were anesthetized, blood was collectedfor fluocinolone levels and the animals were euthanized. The residual NPfrom 4 of the 5 animals per treatment group was collected and weighed.Tissue was collected from the remaining animal in each treatment group,fixed in 10% neutral buffered formalin, processed, embedded in paraffin,sectioned and stained with hematoxylin ad eosin for histologicalevaluation. A single slide was prepared through the center of thesecond, distant subcutaneous pocket containing surgical lesions (Shamcontrol-Group 1), the fluocinolone-eluting pellet (Group 2), or thecontrol pellet (Group 3) but no NP. Slides were evaluated for theinflammatory response and the extent of residual NP. For NP containingtissue, slides were labeled: A, AA, B, BB, C or CC as depicted inFIG. 1. For the distant subcutaneous pocket, a single cross-section wasobtained and the slide was labeled D.

Group 1: Animal 267 (sections A, AA, B, BB, C, and CC): A cross sectionand lateral margins through the site of NP implantation were evaluated.Residual NP was visible in sections A, AA, B and BB. Residualinflammation, but not NP was observed in sections C and CC. The residualNP had lost the majority of its basophilic amorphous appearance and waslargely replaced by large eosinophilic foamy macrophages. Foamymacrophages containing residual NP were surrounded by a fairly thin,pseudo epithelial layer consisting of well organized loose connectivetissue, and smaller numbers of monocytes, macrophages and occasionalneutrophils. Inflammatory cells occasionally extended into the subjacentdermis and muscularis. Representative examples of the changes aredepicted in FIGS. 2-4. FIG. 2 shows a slide of animal 267 at 4×objective with reference being made to the skin surface 1, subcutaneousfat 2, subcutaneous muscle 3, inflammatory response 4, residual NP 5 anddeep muscle layer 6. FIG. 3 shows a slide of animal 267 at 10× objectivewith reference being made to inflammatory response 7 and residual NP 8.FIG. 4 shows a slide of animal 267 at 20× objective with reference beingmade to residual NP 9. Note that reference 9 shows a foamy appearanceand cellular dots that are interpreted as foamy macrophages involved inphagocytosis.

Group 2: Animal 266 (sections A, AA, B, BB, C, and CC): A cross sectionand lateral margins through the site of NP implantation were evaluated.Residual NP was detected only in section C. Sections A, AA, and CCcontained pseudo epithelial pockets and inflammation, but the center ofthe pocket was empty. Sections B and BB appear to be outside of theoriginal site, in that they did not contain NP or residual inflammatoryinfiltrates and consisted of normal tissue. The residual NP waspredominantly acellular and retained its basophilic staining qualitieswith a small to moderate number of foamy macrophages embedded within theresidual NP matrix. The residual NP was most commonly surrounded by adensely cellular, relatively thick, pseudo epithelial layer consistingof fairly well organized loose connective tissue, monocytes, macrophagesand small of neutrophils. Inflammatory cells occasionally extended intothe subject dermis and muscularis. Representative examples of thechanges are depicted in FIGS. 5-7. FIG. 5 shows a slide of animal 266 at4× objective with reference being made to the muscle 10,inflammation/pseudocapsule 11, NP 12, inflammation/pseudocapsule 13,muscle 14, and subcutaneous fat 15. FIG. 6 shows a slide of animal 266at 10× objective with reference being made to inflammation 16 and NP 17.FIG. 7 shows a slide of animal 266 at 20× objective with reference beingmade to residual NP 18, showing a reduced number of macrophages.

Group 3: Animal 265 (sections A, AA, B, BB, C, and CC): A cross sectionand lateral margins through the site of NP implantation were evaluated.NP (characterized by an amorphous, lightly basophilic and poorlycellular material) was observed in the cross sectional slides (A andAA), but not the slides representing the lateral margins (B, BB, C orCC). Variable amounts of NP remained depending upon the sectionevaluated. In some areas of the slide, the residual NP was largelyacellular and retained its basophilic staining qualities (approximately50%). In other areas, the NP had a foamy, lightly eosinophilic andmoderately cellular appearance that was interpreted as partialphagocytic degradation of the NP by foamy macrophages. The residual NPwas most commonly surrounded by a densely cellular, relatively thick,pseudo epithelial layer consisting of fairly well organized looseconnective tissue, monocytes, macrophages and a small number ofneutrophils. In other areas, (not depicted in the figures), the residualNP was surrounded by very loosely arranged spindle shaped cells embeddedin a lightly basophilic amorphorous matrix interpreted as loose newconnective tissue. Inflammatory cells occasionally extended into thesubjacent dermis muscularis. Representative examples of the changes aredepicted in FIGS. 8-10. FIG. 8 shows a slide of animal 265 at 4×objective with reference being made to the muscle 19,inflammation/pseudocapsule 20, NP 21, and inflammation/pseudocapsule 22.FIG. 9 shows a slide of animal 265 at 10× objective with reference beingmade to NP 23 and inflammation 24. FIG. 7 shows a slide of animal 265 at20× objective with reference being made to residual NP 25, showing areduced number of macrophages.

Distant Implant Site/Sham Subcutaneous Pocket: Two-step sections of across section through the “sham pocket” or distant implant site wereevaluated for each animal [Animal numbers 265 (Group 3), 266 (Group 2)and 267 (Group I)]. All of the sham implant sites had a similarhistological appearance and are described together. Skin sections werecharacterized by focally extensive subcutaneous areas of inflammatorycells, eosinophilic debris, and small amounts of collagen. In someareas, there were small, often linear, empty pockets lined by a pseudoepithelial layer of cells and small amounts of collagen. Theinflammatory component was predominantly mononuclear, monocytes andlesser numbers of macrophages with occasional clusters of neutrophils.Cross sections of displaced hair shafts were occasionally noted in thearea of inflammation. Inflammatory infiltrates extended, in some places,into the subjacent muscular layer and overlying dermal tissue. Thechanges observed in these sections are consistent with normal woundhealing and are appropriate for the time period since experimentalinjury. Evidence of the test or control pellets implanted in animals 266(Group 2) or 265 (Group 3) were not visible in the sections evaluated.Representative examples of the changes are depicted in FIGS. 11-12. FIG.11 shows a slide of animal 267D at 4× objective with reference beingmade to the skin surface (epidermis) 26, inflammation 27 and muscle 28.FIG. 12 shows a slide of animal 267D at 10× objective and at 20×objective with reference being made to the pocket 29 and expectedresidual inflammation from surgery 30.

DISCUSSION: There were clear histological differences in the appearanceof the NP implantation sites for Groups 1, 2 and 3. The Group 1 animal(#267), which had a fluocinolone-eluting pellet in the same pocket asthe NP, had the most resorption of the NP material and the leastinflammatory infiltrate surrounding the implanted NP. In animal 267, theNP was almost entirely replaced by large phagocytoic inflammatorymacrophages and was rimmed by only a thin layer of collagen anmononuclear inflammatory cells. This histological evidence is consistentwith the biological mechanism of NP resorption. The Group 2 animal(#266), which had the fluocinolone-eluting pellet in a pocket 1.5 cmfrom the NP material, had much more residual amorphous basophlic NPmaterial and lesser numbers of phagocytotic foamy macrophages in theremaining NP. The inflammatory infiltrate surrounding the NP site wasslightly thicker and contained more inflammatory cells than the group 1animal. The residual NP group mean weights were higher in this group ascompared to Group 1 and support the histological findings of lessresoprtion as compared to Group 1. Finally, the Group 3 animal (#265),which had a control pellet in a pocket 1.5 cm from the NP pocket, hadthe least resorption of the NP material and the greatest inflammatoryinfiltrate surrounding the implant. The group mean NP weights from thegroup were the highest and again are consistent with the histologicaldata.

The fluocinolone eluting pellets did modify the biologic response to NPresorption. This appears to be does dependent based on the assumptionthat a higher does level of fluocinolone would be locally present inGroup 1 animals with the pellet implanted at the same site as comparedto the Group 2 animals in which the pellet was located 1.5 cm away.

1. An implantable drug depot for preventing or reducing pathologicalbone and/or cartilage destruction in a patient in need of suchtreatment, the implantable drug depot comprising fluocinolone in anamount from about 300 micrograms to about 350 micrograms, and at leastone biodegradable polymer, wherein the drug depot is capable ofreleasing fluocinolone or pharmaceutically acceptable salt thereof overa period of at least thirty days.
 2. An implantable drug depot accordingto claim 1, wherein the amount of fluocinolone is between about 300micrograms and about 325 micrograms.
 3. An implantable drug depotaccording to claim 1, wherein the amount of fluocinolone is betweenabout 325 micrograms and about 350 micrograms.
 4. An implantable drugdepot according to claim 1, wherein the at least one biodegradablepolymer comprises one or more of poly(lactide-co-glycolide) (PLGA),polylactide (PLA), polyglycolide (PGA), D-lactide, D,L-lactide,L-lactide, D,L-lactide-caprolactone, D,L-lactide-glycolide-caprolactoneor a combination thereof.
 5. An implantable drug depot according toclaim 4, wherein the at least one biodegradable polymer comprisespoly(lactic-co-glycolic acid) and said poly(lactic-co-glycolic acid)comprises a mixture of polyglycolide and polylactide.
 6. An implantabledrug depot according to claim 5, wherein said mixture comprises morepolylactide than polyglycolide.
 7. An implantable drug depot accordingto claim 1, wherein said fluocinolone comprises fluocinolone acetonide.8. An implantable drug depot according to claim 1, wherein the drugdepot is capable of releasing: (i) a bolus dose of the fluocinolone or apharmaceutically acceptable salt thereof at a joint site; and (ii) aneffective amount of the fluocinolone or a pharmaceutically acceptablesalt thereof over a period of at least thirty days.
 9. An implantabledrug according to claim 1, wherein the at least one biodegradablepolymer comprises poly(lactic-co-glycolic acid) or poly(orthoester) or acombination thereof, and said at least one biodegradable polymercomprises at least 80 wt. % of said drug depot.
 10. A method fortreating arthritis, said method comprising implanting the implantabledrug depot of claim 1 in a person suffering from arthritis at a distanceof less than about 2.0 cm from a target site.
 11. A method according toclaim 10, wherein said distance is less than about 1.5 cm from thetarget site.
 12. A method according to claim 11, wherein said distanceis less than about 1.0 cm from the target site.
 13. A method accordingto claim 10, wherein the arthritis is rheumatoid arthritis.
 14. A methodaccording to claim 10, wherein the arthritis is osteoarthritis.
 15. Amethod according to claim 10, wherein the target site is a joint.
 16. Amethod according to claim 15, wherein the joint is located at an ankle,a toe, a knee, a shoulder, and elbow, a wrist, or a finger.
 17. A methodof treating arthritis in a mammal suffering there from, the methodcomprising locally administering to an affected joint, a biodegradabledrug depot comprising fluocinolone, wherein the fluocinolone reducesdestruction of bone and/or cartilage of the affected joint.
 18. A methodaccording to claim 16, wherein the arthritis is osteoarthritis.
 19. Amethod according to claim 17, wherein the arthritis is rheumatoidarthritis.
 20. A method according to claim 17, wherein the fluocinoloneis in the form of fluocinolone acetonide.